Drug delivery system for implantable cardiac device

ABSTRACT

A drug delivery system incorporated into a cardiac device for delivering a dose of a drug to a patient upon detection of a particular medical condition. The cardiac device may be, for example, an implantable cardioverter/defibrillator, cardiac pacemaker, or combination device that communicates via a radio frequency link with a drug delivery device. The drug delivery device is preferably an electrically modulated transdermal drug delivery device for delivering the drug transdermally in accordance with a signal received from the cardiac device.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/422,433, filed on Oct. 21, 1999 now U.S. Pat. No. 6,361,522, thespecification of which incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to systems and methods for drug delivery and thetherapeutic application of electrical stimulation to the heart forpacing and/or defibrillation. In particular, the invention relates to asystem and method for combining these two modes of therapy.

BACKGROUND

Cardiac pacemakers are implantable devices that replace or supplement aheart's compromised ability to pace itself (i.e., bradycardia) due tochronotropic incompetence or a conduction system defect by deliveringelectrical pacing pulses to the heart. Implantablecardioverter/defibrillators (ICD's) are devices that deliver electricalenergy to the heart in order to reverse excessively rapid heart rates(tachycardia) including life threatening cardiac arrhythmias such asventricular fibrillation. Since some patients have conditions thatnecessitate pacing and also render them vulnerable to life-threateningarrhythmias, implantable cardiac devices have been developed thatcombine both functions in a single device.

Most pacemakers today are operated in some sort of synchronous modewhere the pacing pulses are delivered in a manner that is dependent uponthe intrinsic depolarizations of the heart as sensed by the pacemaker.ICD's must also sense the electrical activity of the heart in order todetect an arrhythmia that will trigger delivery of the shock pulse in anattempt to reverse the condition. Such sensing information could be usedto initiate another mode of therapy, and efforts have been made in thepast to combine automatic drug delivery with either pacemakers, ICD's,or both to treat cardiac arrhythmias. U.S. Pat. No. 5,269,301, forexample, deals with a system for delivering multi-modal therapy at thepatient's bedside in order to treat heart conditions in which pacing,defibrillation, and drug delivery are under the control of a centralprocessor. U.S. Pat. No. 5,087,243 discusses a drug delivery deviceincorporated into an ICD for delivering an antiarrhythmic drugiontophoretically directly to the myocardium via the patch electrodesused for electrical defibrillation upon detection of an arrhythmia. U.S.Pat. No. 5,893,881 describes an ICD with an integrated drug deliverydevice for delivery of a pain medication just prior to the delivery of adefibrillation shock. That patent also contemplates a separateimplantable drug delivery device that communicates with the ICD vialow-frequency radio waves transmitted through the body using a methoddescribed in U.S. Pat. No. 4,897,987.

Implantable drug delivery systems suffer from a number of disadvantages,however. Although the drug reservoir of such a device can bereplenished, it is difficult to change the drug once it is put into thereservoir, making patient management difficult in cases where apatient's condition either changes or otherwise requires a change ofmedication. In addition, drugs degrade over time. Finally, there is therisk of leakage from the reservoir, the consequences of which can rangefrom an annoyance to a medical emergency.

SUMMARY OF THE INVENTION

The present invention is embodied by a drug delivery system incorporatedinto an cardiac device which may be, for example, an implantablecardioverter/defibrillator, cardiac pacemaker, or combination device. Adose of a drug is delivered by the system to a patient upon detection ofa particular medical condition such as an arrhythmia. The drug deliverydevice is preferably an electrically modulated transdermal drug deliverydevice for delivering the drug transdermally in accordance with a signalreceived from the implantable cardiac device. The implantable cardiacdevice communicates via a radio frequency link with the external drugdelivery device.

In one embodiment, an external drug delivery device is designed forexternal affixation to a patient. In the case of an electricallymodulated transdermal drug delivery device, the device is affixed to thepatient's skin surface at a suitable location. The electricallymodulated transdermal delivery injector may have one electrode with adrug reservoir in contact with the skin, another electrode alsocontacting the skin, and a voltage source for imposing a voltage betweenthe electrodes. The device also has a telemetry interface for receivingand transmitting radio frequency signals, circuitry for demodulatingradio signals received from the implantable cardiac device or anexternal programmer to derive a command signal therefrom, and circuitryfor controlling the delivery of the drug in accordance with the commandsignal.

The cardiac device has at least one sensing channel for sensingelectrical activity occurring in a patient's heart and generatingsensing signals indicative of the activity. Circuitry in the deviceextracts information from the sensing signals, which information can beused to detect a particular medical condition, and a command signal isgenerated if the medical condition is present. A telemetry interface forreceiving and transmitting radio frequency signals to the drug deliverydevice is also provided, along with circuitry for modulating the radiofrequency signals with information relating to the command signal.

In another aspect of the invention, an implantable cardiac device withan incorporated drug delivery system is used to detect cardiac ischemiafrom the sensed electrical activity as well as arrhythmias. Upondetection of a cardiac event correlated with ischemia, the device causesdelivery of an appropriate agent such as a thrombolytic, anti-plateletagent, coronary vasodilator, anticoagulant, analgesic, or combination ofsuch agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a system diagram of an exemplary implantable cardiac device.

FIG. 2 is system diagram of the drug delivery device.

DESCRIPTION OF A SPECIFIC EMBODIMENT

In the embodiment to be described, the operations of the implantablecardiac device and the drug delivery device are each controlled bycircuitry which includes a microprocessor executing programmedinstructions in memory. Certain functions could be controlled by customlogic circuitry either in addition to or instead of a programmedmicroprocessor. The term “circuitry” as used herein should therefore betaken to mean either custom circuitry (i.e., dedicated hardware) or amicroprocessor executing programmed instructions contained in aprocessor-readable storage medium along with associated circuitelements.

FIG. 1 is a system diagram of a microprocessor-based implantablecardioverter/defibrillator with the capability of also delivering pacingtherapy. A microprocessor 10 communicates with a memory 12 via abidirectional data bus. The memory 12 typically comprises a ROM forprogram storage and a RAM for data storage. The device has atrialsensing and pacing channels comprising electrode 34, lead 33, sensingamplifier 31, pulse generator 32, and an atrial channel interface 30which communicates bidirectionally with a port of microprocessor 10. Theventricular sensing and pacing channels similarly comprise electrode 24,lead 23, sensing amplifier 21, pulse generator 22, and a ventricularchannel interface 20. (The sensing and pacing channels in thisembodiment use unipolar leads with one electrode attached to each leadand with the case of the device being utilized as a second electrode foreach channel. Other embodiments may use bipolar leads with twoelectrodes attached to each lead.) The channel interfaces 20 and 30include analog-to-digital converters for digitizing sensing signalinputs from the sensing amplifiers and registers which can be written toby the microprocessor in order to output pacing pulses, change thepacing pulse amplitude, and adjust the gain and threshold values for thesensing amplifiers. For each channel, the same lead and electrode areused for both sensing and pacing. The sensing channels are used inconjunction with pacing and for measuring heart rate in order to detecttachycardia and fibrillation. A shock pulse generator 50 is alsointerfaced to the microprocessor for delivering cardioversion ordefibrillation pulses to the heart via a pair of electrodes 51 a and 51b. (In other embodiments, alternative shock electrode configurationswell-known in the art could be used.) A telemetry interface 40 enablesthe device to communicate with an external programmer via modulatedradio frequency waves as well as transmit a command signal to the drugdelivery device upon detection of a particular medical condition such asan arrhythmia. (An external programmer in this context refers to a typeof device for communicating with an implanted device to in order toissue commands affecting its operation or to retrieve status and/orlogged information.)

FIG. 2 is a system diagram of an external drug delivery device fordelivering a quantity of a drug in accordance with a command signalreceived from the implantable cardiac device. The control circuitry ofthe drug delivery device is similar to the implantable cardiac deviceincluding a microprocessor 100, memory 120, and a telemetry interface140 for receiving and demodulating radio signals received from thecardiac device or from an external programmer. A status display 150 isalso interfaced to the microprocessor for displaying information to auser relating to the device's operating status such as battery powerremaining, the amount of drug in the reservoir, and a log of previousdrug deliveries including the amount of drug delivered. Such informationcan also be transmitted either to the implanted cardiac device or anexternal programmer upon receipt of an appropriate query command.

Also interfaced to the microprocessor is a electrically modulatedtransdermal drug delivery voltage generator 130 for generating a voltagebetween electrodes 131 and 132. Electrode 131 is electrically connectedto a drug reservoir 133 which is adapted for contacting the patient'sskin. The term “electrically modulated transdermal drug delivery device”is meant to include any device that uses an electrical field tocontrollably deliver drugs transdermally such as by e.g., iontophoresis,electroporation, electrorepulsion, or electro-osmosis. Electrode 132 isalso adapted for contacting the patient's skin so that when a voltage isimpressed across the electrodes, charged drug molecules are caused tomigrate from the reservoir 133 through epidermal appendages and poresinto the dermal capillary bed where the drug then diffuses into thecirculation. The drug may be in the form of an aqueous solution whose pHis adjusted so that most of the drug is in a charged form, with thepolarity of the electrodes 131 and 132 adjusted for whether the drug isin anionic or cationic form. The drug solution may then be contained inthe reservoir by any medium capable of holding the drug and allowing itsfree flow when subject to an electrical field such as a gauze patch, ora gel or solution with a porous wrapping. The reservoir 133 ispreferably mounted in a frame suitable for affixation to the patientsuch that the reservoir is in contact with skin.

In another embodiment, both electrodes are connected to drug reservoirsso that drugs can be simultaneously delivered from both electrodes. Insuch a configuration, a drug that is positively charged in solution isdelivered from the anode (i.e., the positively charged electrode) whilea second drug that is negatively charged in solution is delivered fromthe cathode. Multiple drug concoctions of similar polarity can also beplaced in the respective anodic or cathodic drug reservoir forsimultaneous delivery. In another embodiment, the same drug is placed inboth reservoirs, with the pH of the solution containing the drugadjusted in each reservoir so that the drug assumes the appropriatecharge for delivery from the electrode connected to that reservoir. Thatis, the pH of the solution is adjusted in each reservoir to be above orbelow the pK of the drug.

In operation, the cardiac device detects a particular medical conditionsuch as an arrhythmia by an analysis of the digitized informationreceived from the sensing channels according to algorithms implementedby the programmed microprocessor 10. Upon detection of a particularcondition indicating the need for drug delivery, a command signal isgenerated which consists of a coded message suitable for transmissionvia the telemetry interface 40. The command signal is then used tomodulate a carrier signal which is received by the drug delivery device.Such a command signal can also be generated and transmitted by anexternal programmer. Upon demodulation of the carrier signal to derivethe command signal, the electrically modulated transdermal drug deliveryvoltage generator 130 is activated by the microprocessor 100 to delivera quantity of the drug to the patient. The command signal can alsocontain information relating to the amount of drug that is to bedelivered by the drug delivery device and/or the time period over whichthe delivery is to take place. In a preferred embodiment, after receiptof the command signal, the drug delivery device generates a statussignal that is transmitted back to the implanted cardiac device orexternal programmer to acknowledge the command. A status signal issimilarly generated and transmitted after the drug delivery operation toverify that the drug has been delivered in accordance with the command.Analysis of further sensing data by the cardiac device in a accordancewith programmed algorithms then allows the effectiveness of the therapyin alleviating the detected medical condition to be assessed and logged.

In another aspect of the invention, drugs other than anti-arrhythmicscan be employed in a drug delivery system such as described above totreat myocardial ischemia. Most patients today who are in need of animplantable cardioverter/defibrillator or pacemaker also suffer fromcoronary atherosclerotic disease which predisposes to acute occlusiveevents due to thrombus formation within the arterial lumina. Since suchevents may precipitate lethal arrhythmias, it may be desirable incertain patients in whom such arrhythmias are correlated with ischemicevents to deliver an anti-ischemia agent to directly affect theocclusive process such as a thrombolytic, an anticoagulant, ananti-platelet agent, or a vasodilator when an arrhythmic condition isdetected. In another embodiment, data from the sensing channels isanalyzed to detect a current of injury in the sensed electrical activityof the heart which indicates myocardial ischemia. Upon detection of suchan ischemic event by the cardiac device, an anti-ischemia agent isdelivered by the drug delivery system.

In another embodiment, the drug or drugs contained in the drug reservoirmay be the same agents as currently being taken orally (or otherwise) bythe patient. The system would detect an arrhythmia or other treatableevent that may be caused by the body concentration of the orallyadministered drug falling below a therapeutic concentration. Once thisevent is detected, a signal from the implantable device causes promptdelivery of the same agent from the external reservoir to restore atherapeutic concentration of the drug. Electrical therapy would also beavailable if needed during this transient recovery period.

In another embodiment, an external drug delivery device as describedabove is used to initiate treatment of a patient with a drug or drugswhere the optimum dosage is not known at the outset. By incorporating asensor or sensors for measuring or detecting a physiological variable inthe drug delivery device, or in a separate device in communication withthe drug delivery device, a feedback loop is formed that enables thedevice to find the drug dosage that produces the desired physiologicaleffect as detected by the sensors. For example, a blood pressuremedication may be administered by the drug delivery device, with thedrug delivery device in communication with a means for continuouslymeasuring blood pressure such as a tonometric manometer. The drugdelivery device would then be programmed to deliver the drug in anamount that attempts to maintain the blood pressure within a specifiedrange. Similarly, an antiarrhythmic drug could be delivered by anexternal drug delivery device that is in communication with a cardiacsensor for detecting arrhythmias. The drug delivery device would thenattempt to administer an amount of the drug that prevents the occurrenceof arrhythmias, increasing or decreasing the amount in accordance withwhether or not arrhythmias are detected by the cardiac sensor. The drugdelivery device would maintain a log of detected events and/or measuredphysiological variables along with the amount of drug delivered over aspecified time period. By downloading the log from the drug deliverydevice (e.g., either with a direct connection or over a telemetry link),a treating physician is able to obtain a record of the response of thepatient over time to the administered drug and formulate an optimum drugdosage schedule for the patient. The drug dosage for the patient maythen be continued, either with the external drug delivery device, orwith a schedule of drug dosages administered orally or otherwise.

Although the invention has been described in conjunction with theforegoing specific embodiment, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Such alternatives, variations, and modifications are intended to fallwithin the scope of the following appended claims.

1. A drug delivery system comprising: an implantable cardiac devicehaving incorporated therein a sensor for sensing a physiologicalvariable in a patient, a first telemetry interface for transmittingradio frequency signals, and circuitry for modulating the radiofrequency signals with a drug delivery command signal; an external drugdelivery device for affixation to a skin surface location on thepatient, the drug delivery device having incorporated therein a secondtelemetry interface for receiving radio frequency signals, circuitry fordemodulating radio signals to derive a drug delivery command signaltherefrom, and circuitry for controlling the drug delivery device inorder to deliver a drug upon receipt of a drug delivery command signal;wherein the implantable cardiac device is programmed to transmit a drugdelivery command signal to the external drug delivery device in responseto the sensed physiological variable in a manner that attempts tocontrol the sensed variable in a closed-loop fashion; and, wherein thesystem is programmed to maintain a downloadable log of the sensedphysiological variable and of the amount of drug administered by thedrug delivery device that can be used to formulate an optimum drugdosage schedule for the patient.
 2. The system of claim 1, wherein theimplantable cardiac device includes a cardioverter/defibrillator.
 3. Thesystem of claim 1, wherein the implantable cardiac device includes apacemaker.
 4. The system of claim 1, wherein the external drug deliverydevice is an electrically modulated transdermal injector comprising: afirst drug reservoir containing a first drug; a first electrode,connected to the first drug reservoir, for contacting the patient'sskin; a second electrode for contacting the patient's skin; and acontrollable power source, connected to the first and second electrodes,to impose a voltage between the first and second electrodes.
 5. Thesystem of claim 4, wherein the transdermal injector further comprises asecond drug reservoir containing a second drug, the second electrode isconnected to the second drug reservoir, and the first and second drugsare simultaneously delivered, respectively from the first and seconddrug reservoirs.
 6. The system of claim 5, wherein the pH of a solutioncontaining the drug in each reservoir is separately adjusted inaccordance with the polarity of the electrode to which the reservoir isconnected.
 7. The system of claim 1, wherein the drug delivered by thedrug delivery device is a vasodilator.
 8. The system of claim 1, whereinthe drug delivered by the drug delivery device is a thrombolytic.
 9. Thesystem of claim 1, wherein the drug delivered by the drug deliverydevice is an anti-platelet agent.
 10. The system of claim 1, wherein thedrug delivered by the drug delivery device is an anti-arrhythmic.
 11. Amethod for drug delivery comprising; sensing a physiological variable ina patient with an implantable cardiac device; generating a commandsignal with the implantable cardiac device in response to the sensedphysiological variable in a manner that attempts to control the sensedvariable in a closed-loop fashion; transmitting the command signal withthe implantable cardiac device to an external drug delivery deviceaffixed to a skin surface location on the patient via a radio telemetrylink; receiving the command signal with the external drug deliverydevice; delivering a drug with the external drug delivery device basedon the command signal; downloading a log of the sensed physiologicalvariable and of the amount of drug administered by the drug deliverydevice; and, using the downloaded log to formulate an optimum drugdosage schedule for the patient.
 12. The method of claim 11, wherein theimplantable cardiac device includes a cardioverter/defibrillator. 13.The method of claim 11, wherein the implantable cardiac device includesa pacemaker.
 14. The method of claim 11, further comprising deliveringthe drug by electrically modulated transdermal injection.
 15. The methodof claim 11, wherein the drug delivered by the drug delivery device is avasodilator.
 16. The method of claim 11, wherein the drug delivered bythe drug delivery device is an anti-arrhythmic.
 17. The method of claim11, wherein the drug delivered by the drug delivery device is athrombolytic.
 18. The method of claim 11, wherein the drug delivered bythe drug delivery device is an anti-platelet agent.